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Invited speaker presentation

Diseases have traditionally been defined predominantly by clinical criteria, sometimes
with the assistance of “conventional” laboratory data. Recent advances in genomic
technology have begun to find previously undiscovered sub-divisions within what were
thought to be single diagnoses, sometimes with significant clinical implications.
This talk will discuss the potential for such technologies to redefine the classification
and treatment of autoimmune diseases, using two recent examples from Cambridge.

The first is the use of a Genome Wide Association Study to determine the genetic underpinning
of ANCA-associated Vasculitis (AAV). This study has confirmed a genetic component
to AAV pathogenesis, and demonstrated that the AAV clinical syndromes granulomatosis
with polyangiitis (GPA: formerly Wegener’s) and microscopic polyangiitis (MPA) are
genetically distinct diseases better defined by ANCA specificity for proteinase-3
(PR3) or myeloperoxidase (MPO) rather than clinical syndrome. In addition the response
against the autoantigen PR3 (encoded by PRTN3) was found to be a central etiological feature of PR3-ANCA associated vasculitis.
Thus PR3- and MPO-ANCA-associated vasculitis must be considered as distinct autoimmune
syndromes [1].

The second example will describe the use of whole genome transcriptome analysis of
purified CD8 T cells to define two sub-groups within patients with a number of inflammatory
diseases (including SLE, AAV, Crohn’s disease and ulcerative colitis). These otherwise
“invisible” groups have markedly different long term outcomes [2,3]. This has implications for therapy, and has led to the development of a biomarker
now entering clinical trials. Follow-up studies have led to the discovery of a new
inflammatory pathway controlling TNFα and IL-10 production that might drive this difference
in outcome.